Energy-Driven Activation of Platinum(IV) Prodrugs: Emerging Strategies for Precision Chemotherapy

Platinum(II)-based chemotherapeutics remain a cornerstone in solid tumor oncology but are severely constrained by systemic toxicities and drug resistance. Platinum(IV) (Pt(IV)) prodrugs have emerged as a powerful platform to circumvent these limitations, capitalizing on their kinetic inertness during systemic circulation and selective activation within reductive microenvironments to release cytotoxic Pt(II) species and bioactive axial ligands. However, traditional endogenously activated Pt(IV) complexes frequently suffer from premature reduction, leading to off-target toxicity in healthy tissues. To address these bottlenecks, the deployment of energy stimuli, including visible/near-infrared light, ultrasound, and ionizing radiation (x-rays/radionuclides), has enabled an emerging strategy toward the spatiotemporally controlled activation of Pt(IV) prodrugs for precision chemotherapy. This review comprehensively encapsulates recent breakthroughs in energy-triggered small-molecule Pt(IV) prodrugs. We categorize and analyze these systems into photoactivatable, tumor-targeting, organelle-specific, ultrasound-responsive, and radiochemically activatable designs. Within each section, the underlying chemical design principles, responsive activation mechanisms, and in vitro/in vivo therapeutic efficacies are elucidated. Finally, we address current clinical translation barriers, including dark stability, hypoxic resistance, and dosimetry inconsistencies, offering a rational roadmap for the development of next-generation, clinically translatable, smart platinum therapeutics.